**6. Current applications**

little was known about the composition and functions of this microbial community, and as such were not thought as agents to be considered in health and disease. Now, we are just beginning to scratch the surface of the potentials of this novel 'organ', and its implication in the overall health of humans. It is referred to as an 'organ' because the gut microbiome (the gut microbiota, gut microbial genomes, and the living environment) is made of millions of bacterial cells that collectively weigh about 1.5 kg, possesses about 150 times more genes than human genes, and contribute significantly to human health. As a result of advances in research, scientists are beginning to appreciate the beneficial roles of gut microbes, and their symbiotic relationship with us, their host. Although previously thought to be responsible for the production of essential vitamins B and K alone, the gut microbiota has been discovered to be implicated in various aspect of human health, and its effects extend beyond the gastrointestinal tract through the release of biosynthesized metabolites (by the gut microbes) from the gut into the systemic circulation. For example, the response of immune cells to inflammation is modulated by the gut microbiota [55]. The effect of these metabolites extends even to the

120 Antimicrobial Resistance - A Global Threat

central nervous system where they influence behavior, mood, and emotions.

by gut commensals include phenols, ammonia, bacteriocins, and ammonia [56].

The composition of the gut microbiota can be positively or negatively affected by dietary habits and other lifestyle factors, the use of antibiotics, age, the state of health, and surgery amongst other factors [57]. The regular consumption of a fiber-rich, plant-based diet improves the compositional profile of the gut microbiota in terms of richness and diversity, and also improves the functional capabilities of the members of the gut microbiota. Good lifestyle practices such as the consumption of fiber-rich foods and fruits increases the relative abundance of beneficial gut microbes which produce metabolites that are responsible for overall gut epithelial health [58]. The impact of diet on the stability of the gut microbiota cannot be overemphasized. This is

In the gastrointestinal tract, the gut microbiota protects the gut against invading pathogens by competing with them for nutrients and attachment site. Most of the antibiotic-resistant disease-causing infectious agents that invade the gastrointestinal tract are food-borne or water-borne, and they include *Salmonella*, *Shigella*, *Campylobacter*, and *Listeria monocytogenes*. On the other hand, the gut microbiota is dominated by members of the Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Other less dominant bacterial phyla include the Fusobacteria, Tenericutes, Spirochaetes (differentially abundant in the gut of hunter-gatherers and rural individuals who consume plant-based foods), Elusimicrobia, and Verrucomicrobia. *Prevotella*—a member of the phylum Bacteroidetes—has also been found to be more abundant in individuals whose lifestyle resembles those of the Paleolithic (such as the hunter-gatherers) and Neolithic (such as the subsistence agriculturalists) era. Conversely, *Bacteroides*—another member of Bacteroidetes—is more abundant in populations that practice a westernized lifestyle, characterized by high-fat, low-fiber diet. Many of the gut commensals such as *Eubacterium*, *Ruminococcus*, *Roseburia*, and *Faecalibacterium* are members of the Firmicutes that produce short-chain fatty acids (such as butyrate, acetate, and propionate) as a product of microbial fermentation (the breakdown of complex polysaccharides), and these acids diminish diarrhea and gastrointestinal inflammation. These short chain fatty acids (SCFA) also create a harsh environment for the colonization of invading gastrointestinal pathogens by the reduction of intestinal pH. Other pathogen-inhibiting metabolites produced

The beneficial role played by bacteria in ingested fermented foods was linked to increased longevity in Balkans [61]. The administration of probiotics has also reduced the shedding of a pathogenic serotype of *E. coli* (*E. coli* O157: H7) by farm animals, thereby reducing the spread of these resistant strains from animals to humans who handle them regularly [62]. Also, there is hope that probiotics wills soon replace antibiotics in the veterinary field to treat diseases of farm animals while enhancing the growth of these farm animals. This way, antibiotic-resistant zoonotic pathogens do not re-emerge and enter the food chain. Also, the cost of production and maintenance of livestock will drop significantly if probiotics are being utilized rather than antibiotics.

Researchers and clinicians are getting conscious of the fact that probiotics isolated from the host have a higher tendency to remain endogenous when administered than probiotics gotten from other sources. This fact informs their decision on the choice of probiotics to be administered. Capsules of probiotics are sometimes used in concert with antibiotics to treat particular diseases with greater effect than if either of them (probiotics or antibiotics) was used alone [17]. This co-administration is done with the hope that this action will reduce antibiotic selective pressure, and decrease the emergence of drug-resistant pathogens. Currently, research is ongoing on the packaging of lyophilized lactic acid bacteria into capsules so that they can be used in the veterinary field (as probiotics) to inhibit the proliferation of zoonotic pathogens [36]. This method will limit the spread of diseases from animals to humans through animal-derived products. Probiotics have been introduced into milk, formula, and other infant foods as a supplement, in order to improve the human gut microbiota stability and tap into the purported benefits of probiotics. The viability of probiotics is enhanced in its lyophilized state within low-fat milk or fruit juice by food formulators and manufacturers [22]. The improvement of the viability of probiotic strains can also be achieved by microcapsulation—a formulation approach that employs the use of microcapsules to package solids, liquids, or gases where these contents could be released in a controlled manner under specific conditions [22]. With this technique, the formulation, storage, and successful transport of probiotic strains to their destination in the gut is assured. Although probiotics are generally regarded as safe, there is a conscious effort to confirm that they do not carry and transfer genes conferring antimicrobial resistance, as this will defeat the purpose of probiotics usage [63]. By and large, the ultimate aim of the use of probiotics is to ensure the stability of the human and animal gut microbiota so as to take advantage of the symbiotic activity of the probiotic and the gut microbial community in the fight against multi-drug resistant gastrointestinal pathogens [8].

procedure, and the fact that there is a risk of undetected pathogens/diseases transfer from the donor to the recipient, some scientists advocate for an alternative to FMT. They believe that isolation and identification of the key players in the restoration of gut microbiota balance will help in the design of a consortium of these microbial players. An artificial stool could be prepared using this donor-sourced purified consortium of gut bacteria which would then replace the use of the donor stools in a less risky, more efficient and more mentally-acceptable

Beneficial Microbes: Roles in the Era of Antimicrobial Resistance

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As previously mentioned, MET is one proposed alternative to FMT. Apart from the fact that this procedure is less disgusting and less risky than FMT, it has the potential to be regulated and standardized more efficiently than FMT [67]. MET procedure involves the isolation, characterization, and screening of gut microbes (for antibiotic resistance, presence of virulence determinants, etc.) from a healthy donor. Gut microbes that pass the screening test will then be recombined into a microbial ecosystem where their combined efforts and synergistic relationships will be more effective in tackling invasive enteropathogens and opportunistic pathogens such as *Clostridium difficile* [68]. In the future, this consortium of synergistic gut microorganisms will be packaged and lyophilized in their live form into capsules and prescribed as a drug. MET is still in its infancy, and it also has to go through regulatory procedures just like a drug, and standardized before it is globally accepted for use in treating gastrointestinal diseases such as antibiotic-induced diarrhea as a therapeutic alternative measure to antibiotic administration. Nevertheless, it offers a promising and a more effective alternative to the use of FMT. Furthermore, since the exact composition of the consortium is defined, it will be easy to track the long-term effect of this potential drug on human health. Also, questions about the interaction between the consortium and the resident gut microbiota and their combined effect on the health of the human host will be answered in detail when this emerging procedure is studied in detail (which can be aided by adequate funding and government support) [67]. In the future, these studies will also open our eyes to the benefits MET has over FMT, and whether there are risks associated with the MET procedure. This information will give the medical community a holistic idea about the merits and demerits of the MET procedure, and will allow the medical practitioners (and patients) to make an informed decision on whether to use MET or stick to FMT or antibiotic administration (or a combination of either two of the three options, or combination of the three options). It will also be interesting to find out whether the MET procedure will be effective in the treatment of

For the advancement of personalized medicine, another prospect is the use of antimicrobial peptides and/or nucleic acid-based methods to selectively kill pathogenic microorganisms in the gut without compromising the structure or function of the gut microbiota (a prominent demerit of antibiotics usage) [69]. Probiotic strains and the gut microbiota have also been thought of as reliable sources of new antimicrobial peptides and antimicrobials, such as bacteriocins [70]. This is because of the complex interaction between the microbial community and

manner [66]. This burgeoning field is known as Microbial Ecosystem Therapeutics.

**7. Future directions**

extra-intestinal diseases in the nearest future [67].

Probiotics are most commonly sold as foods or food supplements, powders, lozenges, tablets (could be chewable, enterocoated or not), sticks, capsules, bottle caps, sachets, stick packs, and oil suspensions (usually for babies) probiotic nasal spray and ointments have also been developed. Most probiotic products available in the market are dairy based foods, including fermented milks, yogurts, cheese etc. The health claims on most probiotics labels tend to be general and such products are intended for the general healthy population. However, manufacturers, food companies, and the media have dispersed unproven information about the purported health benefits of probiotics even before a comprehensive clinical trial has been conducted to validate the efficacy, and the risk–benefit association In terms of probiotics acceptability, although probiotics have been used in the food industries for decades, the discovery of novel strains and genetic manipulation of known strains (some of which are pathogenic) is usually accompanied with a mirror image of the consumer skepticism associated with the marketing of genetically modified foods.

Another current application of beneficial gut microbes is the method of fecal microbiota transplantation (FMT). Fecal microbiota transplantation is a technique that involves the reconstitution of the deliberately-emptied gut of gastrointestinal-diseased patients with the gut microbiota of healthy donor as a therapeutic alternative measure to antibiotic administration for the restoration of the healthy gut microbiota [64]. This method has enabled the majority of those who have been suffering from antibiotic-associated diarrhea and inflammatory bowel diseases to lead a normal life after treatment. Although the filtered donor stool suspension can be passed into the gut of the recipient through rectal enema, nasoduodenal tube, or the nasogastric tube, colonoscopy is the most preferred method of stool suspension transfer. These donor stools could also be lyophilized and packaged into capsules, to be used in treating gastrointestinal infections. Stool banks are currently available in Europe and North America for the storage of tested, pathogen-free donor stools until they are needed by the medical practitioners [65]. Knowledge about the microbial composition of each donor stool and other components of the stool will also inform the medical practitioner and the patient on what to expect after transplantation. Due to the fact that the mental receptiveness of the fecal microbiota transplantation by the patient could have an effect on the effectiveness of this procedure, and the fact that there is a risk of undetected pathogens/diseases transfer from the donor to the recipient, some scientists advocate for an alternative to FMT. They believe that isolation and identification of the key players in the restoration of gut microbiota balance will help in the design of a consortium of these microbial players. An artificial stool could be prepared using this donor-sourced purified consortium of gut bacteria which would then replace the use of the donor stools in a less risky, more efficient and more mentally-acceptable manner [66]. This burgeoning field is known as Microbial Ecosystem Therapeutics.
